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No Differences Between Equivalent Doses of LSD, Mescaline, and Psilocybin, Study Finds
Acute subjective effects reported by healthy individuals given moderate-to-high doses of three psychedelics were extremely similar.
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There are no significant differences in the effects of LSD, mescaline, or psilocybin when given at equivalent doses, according to a new study.
Published in the journal Neuropsychopharmacology, the study directly compared the effects of the three psychedelics in a randomized, double-blind, placebo-controlled cross-over trial. The researchers found that the acute subjective effects reported by healthy individuals given moderate-to-high doses of the drugs were extremely similar; many participants were unable to identify the drug given at any one administration session.
Given the similarity between the altered states of consciousness caused by the drugs at equivalent doses, the researchers say that the dosing information contained in this trial could be useful evidence for future dose-finding studies for psychedelic-assisted therapy.
Different psychedelic trips show strong similarities
A total of 32 healthy volunteers were enrolled in this study, which took place over five sessions in a hospital environment.
At each session, baseline physiological measurements were taken before participants were given either a moderate-to-high dose of mescaline, LSD, or psilocybin, or an equivalent placebo medication designed to be visually identical to active drugs. Following administration, each participant was kept in the hospital for around 25 hours for further observations.
Each participant was asked at regular intervals to rate various aspects of their experience according to multiple validated assessment scales, including the Adjective Mood Rating Scale (AMRS), 5 Dimensions of Altered States of Consciousness scale (5D-ASC), and the States of Consciousness Questionnaire (SOCQ).
Blood pressure, heart rate, pupil diameter, and body temperature metrics were all also frequently monitored in the 24 hours following drug administration. Participants were asked to provide blood samples at baseline, 1.5, 3, and 6 hours after administration, which were assessed for any changes in plasma oxytocin concentration.
The researchers found that the subjective acute drug effects were rated similarly by the study participants across all three drugs. The physical effects of the drugs were also similar, with two exceptions: psilocybin induced significantly higher readings in diastolic blood pressure compared to LSD, while LSD showed a trend towards an increased heart rate compared with psilocybin.
The largest difference between the drugs was their pharmacokinetics and the associated duration of the high. The acute effects of the mescaline lasted the longest, followed by LSD, then psilocybin. The researchers determined that mescaline took significantly longer than LSD to reach its maximal plasma concentration and subjective effects. But once this maximum concentration was reached, the drug was eliminated from the body at the same rate as LSD, meaning they had similar comedowns.
“These pharmacokinetic differences between the two substances may be the only clinically relevant pharmacological distinctions between mescaline and LSD,” the researchers wrote.
Dose, not substance, may matter more
Mescaline, LSD, and psilocybin have notable differences in terms of which receptors they interact with. While they do all bind to the serotonin 5-HT2A receptors, mescaline also binds to the 5-HT1A and adrenergic α2A receptors, while LSD acts against the 5-HT2B/2C, 5-HT1A, and dopamine D1-3 receptors. Psilocin (the active metabolite of psilocybin) acts on the 5-HT2A receptor, but also simultaneously inhibits the serotonin transporter.
Despite these differences, the current study shows that the drugs have similar subjective effects on humans. This may suggest that dosing and the desired duration of action could be the most important factors when it comes to choosing a psychedelic for use in psychedelic-assisted therapy sessions or similar applications.
“We found no evidence of qualitative differences in altered states of consciousness that were induced by 500 mg mescaline, 100 µg LSD, and 20 mg psilocybin,” the researchers wrote. “This study supports dose finding for research and psychedelic-assisted therapy.”
In a previous study, several researchers from the same group also found no significant differences in the psychedelic trip when comparing equivalent moderate and high doses of LSD and psilocybin.
“These findings indicate that any differences in alterations of consciousness that are induced by mescaline, LSD, and psilocybin are dose-dependent rather than substance-dependent and that their distinct pharmacological profiles do not have a relevant influence on the subjective experience,” the researchers wrote in their latest paper.
“The present study further supports the view that all three substances primarily exert their psychedelic effects through agonistic activity at 5-HT2A receptors.”
Reference: Ley L, Holze F, Arikci D, et al. Comparative acute effects of mescaline, lysergic acid diethylamide, and psilocybin in a randomized, double-blind, placebo-controlled cross-over study in healthy participants. Neuropsychopharmacol. 2023;48(11):1659-1667. doi: 10.1038/s41386-023-01607-2
